Accession Number : ADA582726


Title :   Rapid Countermeasure Discovery against Francisella tularensis Based on a Metabolic Network Reconstruction


Descriptive Note : Journal article


Corporate Author : BIOTECHNOLOGY HIGH PERFORMANCE COMPUTING SOFTWARE APPLICATIONS INST FREDERICK MD


Personal Author(s) : Chaudhury, Sidhartha ; Abdulhameed, Mohamed D ; Singh, Narender ; Tawa, Gregory J ; D'haeseleer, Patrik M ; Zemla, Adam T ; Navid, Ali ; Zhou, Carol E ; Franklin, Matthew C ; Cheung, Jonah


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/a582726.pdf


Report Date : 21 May 2013


Pagination or Media Count : 15


Abstract : In the future, we may be faced with the need to provide treatment for an emergent biological threat against which existing vaccines and drugs have limited efficacy or availability. To prepare for this eventuality, our objective was to use a metabolic network-based approach to rapidly identify potential drug targets and prospectively screen and validate novel small-molecule antimicrobials. Our target organism was the fully virulent Francisella tularensis subspecies tularensis Schu S4 strain a highly infectious intracellular pathogen that is the causative agent of tularemia and is classified as a category A biological agent by the Centers for Disease Control and Prevention. We proceeded with a staggered computational and experimental workflow that used a strain-specific metabolic network model, homology modeling and X-ray crystallography of protein targets, and ligand- and structure-based drug design. Selected compounds were subsequently filtered based on physiological-based pharmacokinetic modeling, and we selected a final set of 40 compounds for experimental validation of antimicrobial activity. We began screening these compounds in whole bacterial cell-based assays in biosafety level 3 facilities in the 20th week of the study and completed the screens within 12 weeks. Six compounds showed significant growth inhibition of F. tularensis, and we determined their respective minimum inhibitory concentrations and mammalian cell cytotoxicities. The most promising compound had a low molecular weight, was non-toxic, and abolished bacterial growth at 13 mM, with putative activity against pantetheine-phosphate adenylyltransferase, an enzyme involved in the biosynthesis of coenzyme A, encoded by gene coaD. The novel antimicrobial compounds identified in this study serve as starting points for lead optimization, animal testing, and drug development against tularemia.


Descriptors :   *ANTIMICROBIAL AGENTS , *DRUGS , *FRANCISCELLA TULARENSIS , ASSAYING , CRYSTAL STRUCTURE , CYTOTOXINS , GENES , LIGANDS , METABOLISM , PHARMACOKINETICS , PROTEINS


Subject Categories : Medicine and Medical Research
      Microbiology
      Pharmacology


Distribution Statement : APPROVED FOR PUBLIC RELEASE